CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy with limited therapeutic options. We have previously reported that the transmembrane protein podocalyxin (PODXL) promotes survival of high grade serous carcinoma (HGSC) spheroids against chemotherapy agent carboplatin and NK cell cytotoxicity, and that silencing PODXL by gene editing significantly sensitizes HGSC cells to these treatments. Progesterone, a widely used hormone, has been reported to down-regulate PODXL in endometrial epithelial cells. METHODS: In this current study, we investigated whether progesterone could also lower PODXL in HGSC spheroids to sensitize them to carboplatin and NK cells. Kuramochi cells, a high PODXL expressing HGSC model, was first used to examine the effect of progesterone on PODXL expression. Cells were treated with progesterone or a vehicle control and PODXL levels were assessed. Kuramochi spheroids were then generated from pre-treated cells and exposed to carboplatin to evaluate changes in chemotherapy sensitivity. To assess immune susceptibility, spheroids were co-cultured with primary human NK cells isolated from peripheral blood mononuclear cells, and the effects were examined following 24, 48, and 72 h of co-culture. Additionally, primary HGSC cells were treated with progesterone to assess its ability to modulate PODXL expression in patient-derived samples. RESULTS: Progesterone pre-treatment significantly reduced PODXL expression in Kuramochi spheroids resulting in increased sensitivity to carboplatin and increased NK cell infiltration and cytotoxicity. Furthermore, progesterone showed potential to reduce PODXL expression in ascites-derived primary HGSC cells. CONCLUSIONS: These findings suggest that further studies should explore the utility of progesterone-mediated down-regulation of PODXL in HGSC cancer to increase responsiveness to chemotherapy and NK cells.